Dynamic Simulations of 13 TATA Variants Refine Kinetic
Hypotheses on Sequence/Activity Relationships
The fundamental relationship between DNA sequence/deformability
and biological function has attracted numerous experimental
and theoretical studies. A classic prototype system used for such
studies in eukaryotes is the complex between the TATA element
transcriptional regulator and TBP.
The recent crystallographic study of Burley and co-workers
demonstrated the remarkable contrast between the structural similarity
and different transcriptional activity of 11 different TBP/DNA complexes
(in which the DNAs differed by single bps from each other).
By simulating these TATA variants
and two other single bp variants that were not crystallizable,
we uncover sequence-dependent structural, energetic,
and flexibility properties that tailor TATA elements to TBP interactions,
complementing many previous studies.
Such factors that combine to produce favorable elements for TBP activity
include overall flexibility; minor groove widening,
as well as roll, rise, and shift increases at the ends of the TATA element;
untwisting within the TATA element
accompanied by large roll at the TATA element ends;
and relatively low maximal water densities around the DNA.
These factors work with the severe deformation induced
by the minor-groove binding protein, which kinks
the TATA element at the ends and displaces local waters
to form stabilizing hydrophobic contacts.
Interestingly, the preferred bending direction itself
is not a significant predictor of activity disposition,
although certain variants (such as wildtype AdMLP,
and inactive A29, 5'-TA6G-3')
exhibit large preferred bends in directions consistent with their activity
or inactivity (major groove and minor groove bends, respectively).
These structural patterns, identified here and connected
to a new crystallographic study of a larger
group of DNA variants than reported to date,
highlight the profound influence of single-bp DNA variations
on structure, flexibility, and hydration preferences and the evolutionary
complementarity between DNAs and proteins in binding and activity.
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